The antifungal antibiotic validamycin A is a commercially of interest compound due to its wide application in controlling fungal infections of rice plants caused by Rhizoctonia solani (also referred to as Pellicularia sasakii) (Shibata et al., J. Antibiot. (Tokyo) 35:1422-1423, 1982). Structurally, validamycin A includes an unsaturated aminocyclitol unit valienamine, the saturated aminocyclitol unit validamine and glucose. The valienamine moiety is believed to be the pharmacophore of this compound and is also present in a number of other important aminocyclitols, such as the α-glucosidase inhibitors acarbose, the adiposins, the amylostatins, and the trestatins. In addition, the valienamine unit is a synthetic precursor of the clinically used antidiabetic agent voglibose (Horii, J. Takeda Res. Lab. 52: 1-26, 1993).
Due to its high commercial value, efforts have been made by many groups to obtain valienamine by chemical synthesis. During the past twenty years more than a dozen enantiospecific syntheses have been described for valienamine, however, its commercial supply still relies on natural product degradation processes (Asano et al., J. Antibiot. (Tokyo) 37: 859-867, 1984).
As part of efforts to use biosynthetic approaches to generate novel aminocyclitol analogs, the biosynthetic gene cluster of validamycin A was identified in S. hygroscopicus subsp. jinggangensis 5008 (Bai et al., Chem. Biol. 13: 387-397, 2006). Sequencing of the 45 kb DNA fragment containing the gene cluster revealed 16 structural genes, two regulatory genes, five genes related to transport, transposition/integration, tellurium resistance, and another four genes with no identity. Among those believed to be involved in the synthesis of validamycin A in S. hygroscopicus 5008 are the 2-epi-5-epi-valiolone synthase (ValA), the nucleotidyltransferase (ValB), the cyclitol kinase (ValC), the cyclitol epimerase (ValD), the glycosyltransferase (ValG), the putative dehydratase (ValK), the validoxylamine A 7′-phosphate synthase (ValL), the aminotransferase (ValM), and the cyclitol reductase (ValN).